tbuckley/cabot-search huggingface dataset:
FOSL2 promotes VEGF-independent angiogenesis by transcriptionnally activating Wnt5a in breast cancer-associated fibroblasts: Erratum
Authors: Xueying Wan, Shengdong Guan, Yixuan Hou, Yilu Qin, Huan Zeng, Liping Yang, Yina Qiao, Shuiqing Liu, Qiao Li, Ting Jin, Yuxiang Qiu, Manran Liu
Journal: Theranostics (2022)

[This corrects the article DOI: 10.7150/thno.55074.].
Integrin β3-PKM2 pathway-mediated aerobic glycolysis contributes to mechanical ventilation-induced pulmonary fibrosis
Authors: Shuya Mei, Qiaoyi Xu, Yue Hu, Ri Tang, Jinhua Feng, Yang Zhou, Shunpeng Xing, Yuan Gao, Zhengyu He
Journal: Theranostics (2022)

Background: Mechanical ventilation (MV) can induce pulmonary fibrosis. This study aims to investigate whether MV-induced pulmonary fibrosis is associated with aerobic glycolysis and seeks to uncover the underlying mechanisms mediated by integrin β3-pyruvate kinase M2 (PKM2) pathway. Methods: PKM2 knockdown or inhibition, integrin β3 knockout or inhibition and wild-type mice were exposed to MV (20 mL/kg) for 2 h. Results: Mice exposed to MV exhibited increased expression of collagen deposition, and upregulation of α-smooth muscle actin and collagen I in lung tissues. Single cells analysis showed that MV-induced pulmonary fibrosis was associated with increased gene expression of integrin and glycolysis in pulmonary fibroblasts, as well as upregulation of glycolytic products tested by metabolomics. Meanwhile, increased protein level of integrin β3 and PKM2 was confirmed by western blot and immunohistochemistry. Double immunofluorescence staining and flow cytometric analysis showed increased number of fibronectin+/integrin β3+ and fibronectin+/PKM2+ fibroblasts in lung tissues. Furthermore, MV-induced aerobic glycolysis and pulmonary fibrosis were ameliorated after treatment with PKM2 knockdown-AAV and inhibition, or in integrin β3 knockout and inhibition mice. Conclusions: Integrin β3-PKM2 pathway-mediated aerobic glycolysis contributes to MV-induced pulmonary fibrosis. The inhibition of aerobic glycolysis targeting integrin β3-PKM2 pathway may be a promising treatment for MV-induced pulmonary fibrosis.
The metabolic genomic atlas reveals potential drivers and clinically relevant insights into the etiology of esophageal squamous cell carcinoma
Authors: Xuesong Liu, Ruoxi Hong, Peina Du, Di Yang, Meibo He, Qingnan Wu, Lin Li, Yan Wang, Jie Chen, Qingjie Min, Jinting Li, Weimin Zhang, Qimin Zhan
Journal: Theranostics (2022)

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers globally, with a poor prognosis and ambiguous therapy target.As a hallmark of cancer, metabolism reprogramming plays a critical role in the development of ESCC; however, the genomic alterations underlying this reconfiguration are still largely unknown.Methods: We have comprehensively studied the metabolic genomic variations in an integrated ESCC cohort of 490 patients and characterized the somatic alterations associated with various metabolic pathways. Results:The somatic mutations and copy number alterations (CNAs) occurred heterogeneously in all patients.Using CNA-based clustering, we stratified patients into three clusters and Cluster3 with more deletions marked for worse prognosis.Our findings revealed detailed genetic alterations in components of metabolic pathways and highlighted the role of metal ion channel transporters and non-neuronal/ neuronal synapse systems in the development of ESCC.We found a subset of potential metabolic drivers and functionally validated RYR2, MGST3, and CYP8B1 involved in the ESCC-associated malignancy.Another key finding was that we identified 27 metabolic genes with genomic alterations that could serve as independent prognostic factors and figured out two genetic panels that could stratify patients into distinct prognostic groups. Conclusion:Collectively, our study provided a deep insight into the metabolic landscape in ESCC, extending our understanding of the metabolic reconfiguration underlying the genomic basis of ESCC.Furthermore, our findings revealed potential prognostic factors of ESCC, which are expected to contribute to the accurate determination of the prognosis in the clinic.
DDX56 transcriptionally activates MIST1 to facilitate tumorigenesis of HCC through PTEN-AKT signaling
Authors: Hongzhong Zhou, Yiqun Du, Xiafei Wei, Chunli Song, Jianning Song, Nanson Xu, Weihong Huang, Lichan Chen, Fuwen Yao, Duanming Du, Chuanghua Qiu, Lihong Zhong, Yuchen Liu, Dayong Gu, Jin Wang, Yong Xu
Journal: Theranostics (2022)

Rationale: Hepatocellular carcinoma (HCC) is a primary malignancy of the liver that is the leading cause of cancer-related mortality worldwide.However, genetic alterations and mechanisms underlying HCC development remain unclear.Methods: Tissue specimens were used to evaluate the expression of DEAD-Box 56 (DDX56) to determine its prognostic value.Colony formation, CCK8, and EdU-labelling assays were performed to assess the effects of DDX56 on HCC proliferation.The in vivo role of DDX56 was evaluated using mouse orthotopic liver xenograft and subcutaneous xenograft tumor models.Dual-luciferase reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays were performed to examine the effect of DDX56 on the MIST1 promoter.Results: DDX56 expression in HCC tissues was elevated and this increase was strongly correlated with poor prognoses for HCC patients.Functionally, DDX56 promoted HCC cell proliferation both in vitro and in vivo, while mechanistically interacting with MECOM to promote HCC proliferation by mono-methylating H3K9 (H3K9me1) on the MIST1 promoter, leading to enhanced MIST1 transcription and subsequent regulation of the PTEN/AKT signaling pathway, which promotes HCC proliferation.More importantly, the PTEN agonist, Oroxin B (OB), blocked the DDX56-mediated PTEN-AKT signaling pathway, suggesting that treating HCC patients with OB may be beneficial as a therapeutic intervention.Furthermore, we observed that ZEB1 bound to DDX56 and transcriptionally activated DDX56, leading to HCC tumorigenesis.Conclusions: Our results indicated that the ZEB1-DDX56-MIST1 axis played a vital role in sustaining the malignant progression of HCC and identified DDX56 as a potential therapeutic target in HCC tumorigenesis.
Functional imaging and targeted drug delivery in mice and patient tumors with a cell nucleolus-localizing and tumor-targeting peptide
Authors: Renwei Jing, Qian Wang, Lu Chen, Guangtao Li, Ruibin Li, Leijie Zhang, Hongbing Zhang, Bingfeng Zuo, Yiqi Seow, Xin Qiao, Biaobiao Wang, Jingyuan Xu, Jun Chen, Tianqiang Song, HaiFang Yin
Journal: Biomaterials (2022)
Dipstick Urinalysis Screening of Asymptomatic Adults for Urinary Tract Disorders
Authors: Steffie Woolhandler
Journal: JAMA (1989)

We review evidence on the value of dipstick urinalysis screening for hemoglobin and protein in asymptomatic adults. In young adults, evidence from five population-based studies indicates that fewer than 2% of those with a positive heme dipstick have a serious and treatable urinary tract disease, too few to justify screening and the risks of subsequent workup. For older populations, evidence is contradictory and no recommendation can presently be made for or against hematuria screening. A population-based randomized, controlled trial of hematuria screening in the elderly is urgently needed. Proteinuria screening is not recommended in any healthy, asymptomatic adult population, since four population-based studies have found that fewer than 1.5% of those with positive dipsticks have serious and treatable urinary tract disorders. (<i>JAMA</i>. 1989;262:1214-1219)
CD8 coreceptor engagement of MR1 enhances antigen responsiveness by human MAIT and other MR1-reactive T cells
Authors: Michael N.T. Souter, Wael Awad, Shihan Li, Troi J. Pediongco, Bronwyn S. Meehan, Lucy J. Meehan, Zehua Tian, Zhe Zhao, Huimeng Wang, Adam Nelson, Jérôme Le Nours, Yogesh Khandokar, T. Praveena, Jacinta Wubben, Jie Lin, Lucy C. Sullivan, George O. Lovrecz, Jeffrey Y.W. Mak, Ligong Liu, Lyudmila Kostenko, Katherine Kedzierska, Alexandra J. Corbett, David P. Fairlie, Andrew G. Brooks, Nicholas A. Gherardin, Adam P. Uldrich, Zhenjun Chen, Jamie Rossjohn, Dale I. Godfrey, James McCluskey, Daniel G. Pellicci, Sidonia B.G. Eckle
Journal: The Journal of Experimental Medicine (2022)

Mucosal-associated invariant T (MAIT) cells detect microbial infection via recognition of riboflavin-based antigens presented by the major histocompatibility complex class I (MHC-I)–related protein 1 (MR1). Most MAIT cells in human peripheral blood express CD8αα or CD8αβ coreceptors, and the binding site for CD8 on MHC-I molecules is relatively conserved in MR1. Yet, there is no direct evidence of CD8 interacting with MR1 or the functional consequences thereof. Similarly, the role of CD8αα in lymphocyte function remains ill-defined. Here, using newly developed MR1 tetramers, mutated at the CD8 binding site, and by determining the crystal structure of MR1–CD8αα, we show that CD8 engaged MR1, analogous to how it engages MHC-I molecules. CD8αα and CD8αβ enhanced MR1 binding and cytokine production by MAIT cells. Moreover, the CD8–MR1 interaction was critical for the recognition of folate-derived antigens by other MR1-reactive T cells. Together, our findings suggest that both CD8αα and CD8αβ act as functional coreceptors for MAIT and other MR1-reactive T cells.
Clonal Hematopoiesis and Epigenetic Age Acceleration in Elderly Danish Twins
Authors: Mette Soerensen, Morten Tulstrup, Jakob Werner Hansen, Joachim Weischenfeldt, Kirsten Grønbæk, Kaare Christensen
Journal: HemaSphere (2022)

Clonal hematopoiesis of indeterminate potential (CHIP) is common in the elderly and has been reported to associate with accelerated epigenetic age (AgeAccel), especially intrinsic (ie, cell-type independent) AgeAccel and to a lesser degree extrinsic AgeAccel, which reflects the immune-cell composition of the peripheral blood. We investigated the association between CHIP occurrence and AgeAccel in 154 Danish twin pairs aged 73-90 years (mean 79), using both individual-level and intrapair analyses, the latter to control for shared genetic and environmental factors. Of 308 individuals, 116 carried a CHIP mutation. CHIP carriers had non-significantly increased AgeAccel compared with non-carriers; the strongest association was for the Intrinsic Epigenetic Age Acceleration (IEAA) estimator (CHIP carriers 1.4 years older, P = 0.052). In intrapair analyses, the extrinsic Hannum age estimator showed the strongest association (1.6 years older, P = 0.027). In mutation-specific analyses, TET2 mutations were associated with the extrinsic Hannum age estimator in both individual-level (3.0 years older, P = 0.003) and intrapair analyses (2.8 years older, P = 0.05). DNMT3A mutations were associated with IEAA in individual-level (1.9 years older, P = 0.034) but not intrapair analysis (0.9 years, P = 0.41). Analyses of logit-transformed variant allele frequency were generally consistent with these results. Together, these observations indicate that different factors may be driving the expansion of DNMT3A and TET2 clones, respectively. Finally, CHIP carriers accelerated in both the Hannum and the GrimAge age estimators did not have an increased mortality risk in our cohort followed for 22 years (HR = 1.02, P = 0.93), hence not replicating the stratification model proposed by Nachun et al.
Bortezomib prodrug catalytic nanoreactor for chemo/chemodynamic therapy and macrophage re-education
Authors: Yanjuan Huang, Zilin Guan, Lingling Ren, Yong Luo, Meixu Chen, Yue Sun, Yuanfeng He, Zishan Zeng, Xiuling Dai, Jingwen Jiang, Zeqian Huang, Chunshun Zhao
Journal: Journal of Controlled Release (2022)
The Discovery of Endothelium-Derived Relaxing Factor and Its Importance in the Identification of Nitric Oxide
Authors: Robert F. Furchgott
Journal: JAMA (1996)

The discovery of endothelium-derived relaxing factor (EDRF) and its importance in the identification of nitric oxide (NO) originated with studies using rabbit aorta to examine drug-receptor interactions in vascular smooth muscle. Smooth muscle relaxation by acetylcholine and a number of other agonists was found to be dependent on the presence of endothelial cells, which, when stimulated by the agonist, released a diffusable, very labile, nonprostanoid substance, termed EDRF, that acted on vascular smooth muscle cells to activate relaxation. The characteristics of EDRF, when released from endothelial cells, were similar to the characteristics of NO. It is now established that EDRF, either as NO or some related nitrosyl substance, has a major role in a variety of important biological processes, including the regulation of vascular tone, local blood flow, and blood pressure, inhibition of platelet aggregation and adhesion, and involvement in postischemic reperfusion, memory function, and central nervous system degenerative diseases.
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

A metalloendopeptidase, nardilysin (NRDC), has been suggested to play important roles in inflammation and several cancer types. Yoh and colleagues explored the feasibility of serum NRDC as a prognostic biomarker in patients undergoing surgical resection for intrahepatic cholangiocarcinoma (ICC), the second-most common primary liver cancer with high metastatic rate. As a result, high NRDC levels were associated with poorer prognosis. Serum NRDC levels also were correlated with epithelial mesenchymal transition-related genes in primary tumors. Together, serum NRDC can be a clinically relevant tool for predicting the postoperative outcomes of ICC and therefore contribute to develop a treatment strategy.Up to 50,000 thyroidectomies are performed unnecessarily in the United States annually due to the inability to diagnose benign versus cancerous thyroid nodules. By using genome wide DNA methylation analysis of 109 thyroid tissues, Yim and colleagues found that benign nodules differ from adjacent thyroid tissues and malignant nodules. By using tissue specific epigenetic patterns for benign and malignant thyroid nodules, the authors developed a highly accurate thyroid cancer diagnostic test with an estimated 97% PPV and 100% NPV. Thus, a tissue-specific DNA methylation approach has the potential to provide standard-of-care cancer diagnoses for thyroid nodules.The cellular adhesion molecule VCAM-1 is upregulated on vascular endothelial cells in disease. Using mouse models of brain metastases, Cheng and colleagues show that vascular VCAM-1 is expressed early following metastatic seeding in the brain across a number of different tumor types. Moreover, an MR imaging probe targeted to VCAM-1 enabled detection of micrometastatic deposits that were undetectable using the standard clinical diagnostic method of gadolinium-enhanced MRI. This VCAM-1-targeted MRI approach has the potential to drastically alter the management of patients at risk of brain metastasis in existing treatment paradigms and will lead to greater personalization of care.SGK1 is a conserved member of the AG family of serine/threonine kinases that is highly expressed at the tops of intestinal crypts, suggesting a role in differentiation. SGK1 expression is often reduced in colorectal cancer, with poorly differentiated tumors resulting in a worse prognosis. To explore its role in differentiation, Lee and colleagues conducted a multiomics approach to demonstrate that SGK1 re-expression directly promotes the differentiation of colorectal cancer cells, while inhibiting metastatic potential in a mouse orthotopic xenograft model. This work proposes a greater focus upon therapeutic agents that promote tumor differentiation, rather than simply targeting cell survival, for future research.
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

MAIT cells are most enriched in the liver, comprising up to 50% of all intrahepatic T cells. Duan and colleagues aimed at determining the distribution, phenotype, function, and clinical relevance of MAIT cells in human HCC. They found that HCC-infiltrating MAIT cells' cytotoxic capability was significantly impaired with upregulation of PD-1, CTLA-4 and TIM-3. Still worse, infiltrating MAIT cells were reprogramed to a tumor-promoting direction as exemplified by RNA-seq, cytokine secretion profile and in vitro coculture assay, and correlated with dismal clinical outcomes. This study shows promise for modulating MAIT cells' function in antitumor therapy in HCC.Overcoming tumor-related immunosuppression presents a significant obstacle to successful cancer treatment. To activate the host's antitumor immunity, Viitala and colleagues exploited macrophage reprogramming as an alternative approach to stimulate CD8+ T-cell–mediated tumor cell killing. Genetic deficiency or immunotherapeutic targeting of macrophage Clever-1 induced IL-12 secretion and MHCII expression by tumor-associated macrophages, and markedly impaired solid tumor growth in multiple syngeneic mouse tumor models. Notably, the effects were similar to those achieved by PD-1 checkpoint inhibition, and thus support the clinical evaluation of Clever-1 blockade as a novel cancer treatment strategy.NOTCH1 loss-of-function mutations are common in head and neck squamous cell carcinoma (HNSCC). Sambandam and colleagues demonstrate that NOTCH1-mutant HNSCC undergoes cell death when exposed to PI3K inhibitors, which was linked to drug-induced suppression of PDK1. In contrast, PIK3CA mutant cell lines merely undergo cell cycle arrest when exposed to the same drugs. This is the first study to establish a therapeutic vulnerability of NOTCH1-mutant HNSCC to any class of drugs and may inform the development of the first biomarker-driven therapy for HNSCC. This research led to the initiation of a clinical trial testing a PI3K/mTOR inhibitor in NOTCH1 mutant HNSCC (NCT03740100).Chemokine receptor CXCR2 drives immune escape and chemoresistance in human cancers. To explore its role in gastric cancer (GC) metastasis, Zhou and colleagues established the lymph node metastasis model and a coculture system of GC cells and macrophages to demonstrate that macrophages promote migration of GC by activating a CXCR2/STAT3 feed-forward loop in a CXCL1/CXCL5-dependent manner, and GC cells increase the expression of CXCL1/CXCL5 in macrophages by secreting TNF-α. This study identified a CXCR2 dominated cross-talk between GC cells and macrophages, and thus provides a potential therapeutic target for GC treatment.
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

Neuroendocrine tumors (NET) are rare neoplasms arising from diffusive neuroendocrine cells of various organs. Current systemic treatments for advanced or metastatic NET are limited. The clinical effect of VEGFR inhibitors has not been well characterized in extrapancreatic NET. In this phase II study by Xu and colleagues, surufatinib, a novel and selective VEGFR inhibitor, showed potent and durable antitumor activity in patients with well-differentiated advanced NET irrespective of the primary tumor origins; similar antitumor activity was observed in both VEGFR-inhibitor-naïve and pretreated patients. This study provided clinical evidence that surufatinib might be a promising therapeutic candidate for patients with well-differentiated advanced NET.95% of all peptide vaccines focus on cellular T cell immune responses. Bekaii-Saab and colleagues report a new paradigm in immunotherapy that focuses on humoral responses based on chimeric conformational B-cell epitope vaccines. In the phase 1b trial, the combination of two HER-2 peptide B-cell epitope vaccines engineered to represent the trastuzumab and pertuzumab binding sites was safe, exhibited antitumor activity, and showed preliminary indications that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.The retinoic acid-related orphan receptor gamma (RORgamma) is a nuclear receptor transcription factor that acts as an immune cell master control switch through regulation of type 17 effector T-cell differentiation and function. In this phase 1 study, Mahalingam and colleagues evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LYC-55716, a first in class, oral, selective RORgamma agonist. The study established a recommended dose for further study and provided evidence of clinical activity of LYC-55716. Based on the findings of this study, RORgamma agonists may represent a new approach to enhance antitumor immunity for patients with advanced cancers.Immunotherapy is used to treat several types of squamous cell carcinomas (SCC), but response rates are relatively low. In this study, Li and colleagues explored the immune landscape of esophageal, head and neck, lung, and cervical SCC. They identified and validated six immune subtypes, each of which was associated with distinct gene expression profiles, genetic aberrations, tumor-infiltrating immune cell composition and functional orientation, cytokine profiles, and clinical outcomes. This study provides a conceptual framework to understand the complex immune microenvironment of SCC and may have implications for the design of combination treatment strategies and selection of patients for immunotherapy.
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

Treatment options are limited for breast cancer patients with central nervous system (CNS) metastasis. The combination of capecitabine and lapatinib, at conventional doses, has activity against HER2-positive breast cancer brain metastases; however, few patients respond, especially long-term. In this study, Morikawa and colleagues evaluated the safety and toxicities associated with intermittent high dose lapatinib alternating with intermittent fixed dose capecitabine in HER2-positive breast cancer patients with CNS metastasis. This regimen resulted in manageable toxicity and promising efficacy and will inform future phase II/III trials.Hypoxia is a negative prognostic feature in nearly all cancer types and predicts treatment failure. Validated, widely available tests are lacking for clinical use. Salem and colleagues provide the first-in-human evidence that oxygen-enhanced MRI (OE-MRI) can track changes in hypoxia that are induced by radiotherapy. OE-MRI was well-tolerated in patients with non-small cell lung cancer, and radiotherapy-induced hypoxia modification was detected. OE-MRI has potential to select patients for hypoxia-modification, track therapeutic efficacy, and identify tumors that may fail immunotherapy.Immunotherapy has been ineffective for patients with pancreatic ductal adenocarcinoma (PDA). In this study, Seo and colleagues demonstrate that CD8+ T cells are often present in PDA, but are localized to the stroma, rather than immediately adjacent to cancer cells. Using slice culture live microscopy from primary PDA tumors, the authors demonstrate that inhibition of the CXCR4 chemokine receptor led to the migration of clonally expanded CD8+ T cells to the cancer cell-rich regions of the tumors. Subsequent PD-1 blockade activated effective cancer cell killing. These results provide a new basis for the rational selection of combination immunotherapy for PDA, a disease with limited treatment options.Relapse remains a major issue for patients with multiple myeloma due to the presence of minimal residual disease (MRD) posttherapy. Bispecific T cell-engager antibody therapy has been effective in the elimination of MRD in other hematological malignancies. Zuch de Zafra and colleagues describe AMG 424, a novel bispecific T-cell–recruiting antibody targeted at CD3 and CD38, the multiple myeloma surface cell marker. AMG 424 effectively killed CD38-positive cells in vitro and showed antitumor activity in mouse and nonhuman primate models. AMG 424 is a promising candidate for multiple myeloma patients and is currently in clinical development.